Current treatment modalities for primary central nervous system (CNS) and leptomeningeal (LPM) malignancies have proven inadequate. Eradication of LPM disease may be enhanced by direct compartmental therapy of tumor-specific agents maximizing concentration to tumor sites while reducing systemic toxicities. To test this principle, we employed the intrathecal (IT) radiolableled murine monoclonal antibody 3F8 targeting tumor associated GD2 in healthy non-human primates, whose GD2 tissue distribution (DNS and peripheral) is identical to that in humans. We demonstrated that IT 131I-3F8 can deliver a high dose of radiation (up to 82 Gy) to the CSF, with tolerable side effects. Moreover, serum antibody against the MoAb was 1422 fold higher than that in the SF, thereby accelerating blood clearance (reducing blood radiation dose) without affecting CSF pharmacokinetics. We now propose to define the role of compartment radioimmunotherapy by assessing the pharmacokinetics and dosimetry of IT131 I-3F8 in relation to HAMA production, clinical efficacy and toxicity in a phase I dose-escalation (10 to 50 mCi) clinical trial for patients with GD2-expressing CNS malignancies. We further propose to manipulate drug delivery in the thecal space of non-human primates to maximize the CSF:blood ratio. Using genetically engineered anti- GD2 single chain and signs chain-streptavidin constructs differing in both size and binding characteristics, these novel IT agents will be tested in cynomolgus monkeys, the results of which are applicable to human patients. These measurements are critical for the optimization of antibody constructs and other targeted agents that may contribute to more effective treatment modalities for patients with CNS malignancies and related disorders.